Crystallization in amorphous solids can be influenced by preparation methods, formulation ingredients, and storage conditions e.g. temperature and humidity. The solid-state form of an organic powder may influence both its chemical and physical properties. For example, the bioavailability of an active pharmaceutical ingredient may change substantially depending on the solid-state form, with even a trace residual crystallinity significantly affecting shelf life.
Understanding of solid-state phase heterogeneity is currently limited in large part by an inability to accurately quantify the trace crystallinity (<1%) of small organic molecules. Studies of solid state phase transformations, especially in solid powders, have been performed using powder X-ray diffraction (PXRD), Raman spectroscopy, infrared spectroscopy, and differential scanning calorimetry (DSC). Although the detection of low levels of crystallinity (˜0.2%) has been demonstrated with X-ray diffraction, this level of sensitivity requires high-energy X-rays generated by a synchrotron source and is not suitable for routine analysis. Furthermore, the aforementioned methods provide only ensemble-averaged properties, with no microscopic information (e.g., crystal size distributions, crystal nucleation kinetics, or the like), which can be important in mechanistic studies.
An ability to detect the crystal fraction in an amorphous phase, when the crystal fraction is present at low amounts may allow for the detection of residual crystalline solid that is present as a result of incomplete vitrification. Residual crystal seeds may induce and accelerate crystallization via heterogeneous nucleation, which can give rise to biased results especially when crystallization kinetics and mechanism are of interest. Also, detection of crystallinity at sub-percent level can facilitate the screening and designing of the optimal conditions for crystallization control.
One method of introducing phase heterogeneity within organic powders is by mechanical grinding, which has been widely used as a means for reduction of particle size and synthesis of new materials. For pharmaceutical applications, milling has been employed to enhance the dissolution rate through particle size reduction achieved by mechanical milling and this is sometimes performed at cryogenic temperatures (cryomilling) to minimize local heating. Previous studies have shown that mechanical grinding can result in a loss in crystallinity, a phenomenon observed both in inorganic materials and organic compounds that may result in a mixture of solid-state phases within the sample. The loss of crystalline order in active pharmaceutical ingredients (APIs) during mechanical milling may be deleterious since the loss of crystalline order affect the physical and chemical stability of the drug, which may affect the shelf-life of pharmaceutical products. Typically, mechanical grinding induces solid-state phase transformations as a result of the high shear forces experienced by the material, which may lead to a higher energy defective crystalline material which may subsequently undergo a crystal-to-glass transformation.
Although the effects of mechanical processing have been widely documented, aspects of the process remain unknown for organic systems. Studies of mechanically-induced crystallinity loss are generally performed using X-ray diffraction or thermal analysis techniques. The reduction in the intensity of the Bragg peaks in combination with the presence of a diffuse halo is a common characteristic of increasing disorder within a material. A diffuse halo can, however, arise from different macro/nanoscopic orientation described as thermodynamic disordering: e.g., as observed for melt quenches of organic crystal; or, kinetic disordering whereby the long range crystalline order is reduced to the short-range nanocrystalline domains.
Another method of introducing phase heterogeneity is through the formation of crystals within homogeneous amorphous matrices, including glasses and polymers in the form of powders or tablets. The use of amorphous materials is widespread in the design of pharmaceutical formulations, most typically used to kinetically prevent crystal formation by slowing molecular diffusion. Characterizing nucleation and crystallization kinetics in such matrices is important in making to shelf-life assessments in accelerated stability investigations.